1. Field of the Invention
This invention is concerned with improvements in or relating to glucopyranose-nitrosourea compounds.
In particular, the invention relates to a process for the production of glucopyranose-nitrosourea compounds which have antitumor activity. The compounds produced by the process of the invention have the following general formula: ##STR1## in which R.sup.1 represents one member selected from the group consisting of hydroxy group, alkoxy group having from 1 to 4 carbon atoms and N.sub.1 -substituted-1-nitrosourea group of formula ##STR2## (wherein R.sup.8 represents an alkyl group having from 1 to 4 carbon atoms or a 2-chloroethyl group); and R.sup.2 and R.sup.3, which may be the same or different, each represents a hydroxy group or an N.sub.1 -substituted-1-nitrosourea group of formula ##STR3## (wherein R.sup.8 is as defined above); with the proviso that R.sup.1, R.sup.2 and R.sup.3 are not all the same.
Certain compounds of the general formula I are novel and constitute a further feature of the invention. The novel compounds are characterised by the presence of an N.sub.1 -substituted-1-nitrosourea group (as defined above) as substituent at the 6-position carbon of D-glucopyranose skeleton in formula I and have the following general formula: ##STR4## in which R.sup.8 is as defined above.
2. The Prior Art
Various glucopyranose-nitrosourea compounds having antitumor activity have hitherto been disclosed, of which the following compounds have especially been studied in detail:
Streptozotocin (hereinafter referred to as "SZ"); PA1 alkyl streptozotocin (hereinafter referred to as "alkyl SZ"); PA1 1-(2-chloroethyl)-3-(D-glucopyranos-2-yl)-1-nitrosourea (hereinafter referred to as "DCNU"); PA1 1-(2-chloroethyl)-3-(.beta.-D-glucopyranosyl)-1-nitrosourea (hereinafter referred to as "GANU"); PA1 1-(2-chloroethyl)-3-(methyl .alpha.-D-glucopyranos-2-yl)-1-nitrosourea (hereinafter referred to as "2MC.alpha.G"); PA1 1-(2-chloroethyl)-3-(methyl .alpha.-D-glucopyranos-6-yl)-1-nitrosourea (hereinafter referred to as "6MC.alpha.G"); and PA1 3,3'-(methyl .alpha.-D-glucopyranos-2,6-di-yl)-bis[1-(2-chloroethyl)-1-nitrosourea] (hereinafter referred to as "WMC.alpha.G"). PA1 6MC.alpha.G, PA1 3-(methyl .beta.-D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(ethyl .alpha.-D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(ethyl .beta.-D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(n-propyl .alpha.-D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(n-propyl .beta.-D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(n-butyl .alpha.-D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(n-butyl .beta.-D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(methyl .alpha.-D-glucopyranos-6-yl)-1-methyl -1-nitrosourea, PA1 3-(methyl .beta.-D-glucopyranos-6-yl)-1-methyl -1-nitrosourea, PA1 3-(ethyl .alpha.-D-glucopyranos-6-yl)-1-methyl -1-nitrosourea, PA1 3-(ethyl .beta.-D-glucopyranos-6-yl)-1-methyl -1-nitrosourea, PA1 3-(ethyl .alpha.-D-glucopyranos-6-yl)-1-ethyl-1-nitrosourea, PA1 3-(ethyl .beta.-D-glucopyranos-6-yl)-1-ethyl-1-nitrosourea, and PA1 3-(n-propyl .alpha.-D-glucopyranos-6-yl)-1-n-butyl-1-nitrosourea; PA1 2MC.alpha.G, PA1 3-(methyl .beta.-D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(ethyl .alpha.-D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(ethyl .beta.-D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(n-propyl .alpha.-D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(n-propyl .beta.-D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(n-butyl .alpha.-D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(n-butyl .beta.-D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, PA1 3-(methyl .alpha.-D-glucopyranos-2-yl)-1-methyl-1-nitrosourea, PA1 3-(methyl .beta.-D-glucopyranos-2-yl)-1-methyl-1-nitrosourea, PA1 3-(methyl .beta.-D-glucopyranos-2-yl)-1-ethyl-1-nitrosourea, PA1 3-(methyl .alpha.-D-glucopyranos-2-yl)-1-n-propyl--nitrosourea, PA1 3-(ethyl.alpha.-D-glucopyranos-2-yl)-1-ethyl-1-nitrosourea, PA1 3-(ethyl .beta.-D-glucopyranos-2-yl)-1-ethyl-1-nitrosourea, PA1 3-(n-propyl .alpha.-D-glucopyranos-2-yl)-1-methyl-1-nitrosourea, and PA1 3-(n-butyl .beta.-D-glucopyranos-2-yl)-1-methyl-1-nitrosourea; PA1 Wmc.alpha.g, PA1 3,3'-(methyl .beta.-D-glucopyranos-2,6-di-yl)-bis[1-(2-chloroethyl)-1-nitrosourea], PA1 3,3'-(ethyl .alpha.-D-glucopyranos-2,6-di-yl)-bis[1-(2-chloroethyl)-1-nitrosourea], PA1 3,3'-(ethyl .beta.-D-glucopyranos-2,6-di-yl)-bis[1-(2-chloroethyl)-1-nitrosourea], PA1 3,3'-(n-propyl .alpha.-D-glucopyranos-2,6-di-yl)-bis[1-(2-chloroethyl)-1-nitrosourea], PA1 3,3'-(n-propyl .beta.-D-glucopyranos-2,6-di-yl)-bis[1(2-chloroethyl)-1-nitrosourea], PA1 3,3'-(n-butyl .alpha.-D-glucopyranos-2,6-di-yl)-bis[1-(2-chloroethyl)-1-nitrosourea], PA1 3,3'-(n-butyl .beta.-D-glucopyranos-2,6-di-yl)-bis[1-(2-chloroethyl)-1-nitrosourea], PA1 3,3'-(methyl .alpha.-D-glucopyranos-2,6-di-yl)-bis(1-methyl-1-nitrosourea), PA1 3,3'-(methyl .beta.-D-glucopyranos-2,6-di-yl)-bis(1-methyl-1-nitrosourea), PA1 3,3'-(ethyl .alpha.-D-glucopyranos-2,6-di-yl)-bis(1-methyl-1-nitrosourea), PA1 3,3'-(n-propyl .alpha.-D-glucopyranos-2,6-di-yl)-bis(1-methyl-1-nitrosourea), PA1 3,3'-(n-butyl .beta.-D-glucopyranos-2,6-di-yl)-bis(1-methyl-1-nitrosourea), PA1 3,3'-(methyl .alpha.-D-glucopyranos-2,6-di-yl)-bis(1-ethyl-1-nitrosourea), and PA1 3,3'-(n-propyl .beta.-D-glucopyranos-2,6-di-yl)-bis(1-n-propyl-1-nitrosourea); PA1 Dcnu, PA1 3-(d-glucopyranos-2-yl)-1-methyl-1-nitrosourea (i.e. SZ), PA1 3-(d-glucopyranos-2-yl)-1-ethyl-1-nitrosourea, PA1 3-(D-glucopyranos-2-yl)-1-n-propyl-1-nitrosourea, and PA1 3-(D-glucopyranos-2-yl)-1-n-butyl-1-nitrosourea; PA1 3-(D-glucopyranos-6-yl)-1-(2-chloroethyl)-1-nitrosourea (referred to as "6DCNU"), PA1 3-(d-glucopyranos-6-yl)-1-methyl-1-nitrosourea, PA1 3-(D-glucopyranos-6-yl)-1-ethyl-1-nitrosourea, PA1 3-(D-glucopyranos-6-yl)-1-n-propyl-1-nitrosourea, and PA1 3-(D-glucopyranos-6-yl)-1-n-butyl-1-nitrosourea; PA1 Ganu, PA1 3-(.beta.-d-glucopyranosyl)-1-methyl-1-nitrosourea, PA1 3-(.beta.-D-glucopyranosyl)-1-ethyl-1-nitrosourea, PA1 3-(.beta.-D-glucopyranosyl)-1-n-propyl-1-nitrosourea, PA1 3-(.beta.-D-glucopyranosyl)-1-n-butyl-1-nitrosourea, PA1 3-(.alpha.-D-glucopyranosyl)-1-methyl-1-nitrosourea, and PA1 3-(.alpha.-D-glucopyranosyl)-1-ethyl-1-nitrosourea; and PA1 3,3'-(D-glucopyranos-2,6-di-yl)-bis[1-(2-chloroethyl)-1-nitrosourea], PA1 3,3'-(D-glucopyranos-2,6-di-yl)-bis(1-methyl-1-nitrosourea), PA1 3,3'-(D-glucopyranos-2,6-di-yl)-bis(1-ethyl-1-nitrosourea), PA1 3,3'-(D-glucopyranos-2,6-di-yl)-bis(1-n-propyl-1-nitrosourea), and PA1 3,3'-(D-glucopyranos-2,6-di-yl)-bis(1-n-butyl-1-nitrosourea).
The above-mentioned known glucopyranose-nitrosourea compounds have generally been produced by nitrosating glucopyranose-urea compounds of the following general formula, using nitrite or nitrogen trioxide under acidic conditions: ##STR5## in which R.sup.9 represents one member selected from the group consisting of hydroxy group, alkoxy group having from 1 to 4 carbon atoms and N.sub.1 -substituted ureido group of formula ##STR6## (wherein R.sup.8 is as hereinbefore defined); and R.sup.10 and R.sup.11, which may be the same or different, each represents a hydroxy group or an N.sub.1 -substituted ureido group (as defined above); with the proviso that R.sup.9, R.sup.10 and R.sup.11 are not all the same. Compounds of formula III include, for example, 1-(2-chloroethyl)-3-(alkyl D-glucopyranos-6-yl)urea, 1-(2-chloroethyl)-3-(.beta.-D-glucopyranosyl)urea, 1-(2-chloroethyl)-3-(D-glucopyranos-2-yl)urea, 1-(2-chloroethyl)-3-(alkyl D-glucopyranos-2-yl)urea and 3,3'-(alkyl D-glucopyranos-2,6-di-yl)-bis-[1-(2-chloroethyl)urea]. [cf. Journal of the American Chemical Society, 89 (1967), 4808; Journal of Organic Chemistry, 35 (1970), 245; The Journal of Antibiotics, 25 (1972), 377; Journal of Medicinal Chemistry, 17 (1974), 392; ibid., 19 (1976), 918; ibid., 18 (1975), 104; Organic Preparations and Procedures Int., 6 (1974), 259; Bulletin of the Chemical Society of Japan, 48 (1975), 3763; Eur. J. Med. Chem.-Chimica Therapeutica, 11 (1976), 183; German Pat. Offenlegungsschrift No. 2,530,416; Dutch Pat. Offenlegungsschrift No. 7,507,973; Belgian Pat. Offenlegungsschrift No. 832,227; Japanese Pat. Offenlegungsschrift No. 6,925/'76; ibid. 26,819/'76; ibid. 17,423/'77; Ring Doc, 13472P (Derwent Publications Ltd.), 1974; Cancer Treatment Reports, 60 (1976), 801; Cancer Research, 33 (1973), 2005; Proceeding of the Society for Experimental Biology and Medicine, 152 (1976), 195; Gann, 66 (1975), 347; ibid. 67 (1976), 137].
However, it is known that when GANU is produced by the above conventional nitrosating process for producing the glucopyranosenitrosourea compounds of formula I, the isomer having a nitroso group at the N.sub.3 -position, that is, the glucopyranose-nitrosourea compound with an N.sub.1 -substituted-3-nitrosourea group of formula ##STR7## wherein R.sup.8 is as hereinbefore defined, is also formed as a by-product. The antitumor activity of this by-product is 0-30% of that of the desired compound of formula I (cf. op. cit.).